The Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities - TESLA Part B

Description:

Patients with homozygous familial hypercholesterolemia have markedly elevated low-density lipoprotein cholesterol (LDL-C) and early cardiovascular disease. Statins typically reduce LDL-C in such patients by 22-25%. The current trial sought to assess the safety and efficacy of evolocumab, a PCSK9 inhibitor, to further reduce LDL levels in patients with homozygous familial hypercholesterolemia on lipid-lowering therapy.

Hypothesis:

Evolocumab would result in greater LDL reductions than placebo in patients with homozygous familial hypercholesterolemia on baseline lipid-lowering therapy.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel

Patient Populations:

  • Subjects at least 12 years of age with homozygous familial hypercholesterolemia diagnosed by genetic analysis or clinical criteria and on baseline lipid-lowering therapy

    Number of screened applicants: 52
    Number of enrollees: 50
    Duration of follow-up: 12 weeks
    Mean patient age: 31 years
    Percentage female: 49%

Exclusions:

  • Lipoprotein apheresis within the previous 8 weeks
  • Use of mipomersen or lomitapide within the last 5 months

Primary Endpoints:

  • Percent change in LDL from baseline at 12 weeks

Secondary Endpoints:

  • Absolute change in LDL from baseline at 12 weeks
  • Proportion of patients with LDL <70 mg/dl
  • Change in other lipoproteins from baseline

Drug/Procedures Used:

Patients were randomized in a 2:1 fashion to receive evolocumab 420 mg subcutaneously every month versus placebo subcutaneously every month for 12 weeks.

Concomitant Medications:

Statins (100%; 63% on atorvastatin and 38% on rosuvastatin), ezetimibe (94%)

Principal Findings:

A total of 49 patients were randomized, 33 to evolocumab versus 16 to placebo. The mean age was 31 years, and 43% had coronary artery disease. Mean LDL at baseline was approximately 348 mg/dl, and mean high-density lipoprotein (HDL) was 39 mg/dl.

Compared with placebo, evolocumab 420 mg subcutaneously every 4 weeks reduced LDL-C by 30.9% (absolute difference of 93 mg/dl) at 12 weeks (p < 0.0001). Compared with placebo, evolocumab resulted in similar HDL-C -0.9% at 12 weeks (p = 0.98).

No serious treatment-emergent adverse events occurred in either group. The most frequent adverse event with evolocumab was upper respiratory infection in 9%.

Interpretation:

Among patients with homozygous familial hypercholesterolemia, evolocumab 420 mg every 4 weeks resulted in approximately a 30% greater reduction in LDL levels at 12 weeks compared with placebo. Overall, this agent appeared to be well tolerated.

Evolocumab is a monoclonal antibody directed against PCSK9. This study adds to the body of literature with PCSK9 inhibitors which promote hepatic LDL receptor degradation, thereby reducing LDL receptor density and clearance of LDL particles. It is unknown if the use of these agents will result in better cardiovascular outcomes in familial hypercholesterolemia patients, and potentially nonfamilial hypercholesterolemia patients with atherosclerosis. A number of other agents such as cholesteryl ester transfer protein inhibitors and niacin also favorably impacted on multiple lipoproteins, but did not improve cardiovascular outcomes.

References:

Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2014;Oct 1:[Epub ahead of print].

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Proprotein Convertases, Respiratory Tract Infections, Coronary Artery Disease, Cholesterol Ester Transfer Proteins, Follow-Up Studies, Cholesterol, LDL, Homozygote, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Niacin, Receptors, LDL, Lipoproteins, HDL


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